Pharmacokinetics of 7-con-O-methylnogarol in patients with solid tumors

Summary The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m². The drug disappeared from plasma biexponentially with a mean elimination half-life of 38±3 h; the mean apparent volume of distribution and the plasma clearance were 805±91 l/m² and 14±2 l/h per m². Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%–15% and 0.1%–6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.     

Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs

Summary Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m² ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1±4.5 min and the mean elimination half-life was 69±28 min. The mean plasma clearance was 227±125 ml min^–1 m^–2. The peak concentration of ara-C in the CSF was 29±11 m, which occurred at 57±13 min after the ara-C bolus. The CSF elimination half-life was 113±26 min. During a 12-h infusion of ara-C (50 mg m^–2 h^–1), the plasma steady-state concentration was 14.1±4.2 m, the CSF steady-state concentration was 8.3±1.1 m, and the CSF: plasma ratio was 0.62±0.14. The plasma eleimination half-life was 64±19 min and the plasma clearance was 214±69 ml min^–1 m^–2. The CSF elimination half-life was 165±28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.Supported by the Canine Disease Research Fund and in part by the Elsa U. Pardee Foundation     

Clinical pharmacolinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1H-imidazol-2-yl)hydrazone]dihydrochloride

Summary We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120–250 mg/m² IV; one of these patients also received a second dose of 120 mg/m² 6 weeks later, and another received 150 mg/m² weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t_1/2 of 0.6±0.3 h and a terminal t_1/2 of 24.7±6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1±5.9 l/kg, and the total clearance was 1045.5±51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4%±1.1% of the dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t_1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.     

Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone

Summary Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150–600 mg/m²), once a week (200 mg/m² per week), or as 5 daily doses repeated every 28 days (60–180 mg/m² per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9±2.1 h (n=18 doses). The volume of distribution was 3.4±2.6 l/kg and plasma clearance was 629±469 ml/min per m². Several soluble analogues with similar antitumour activity are currently under investigation.This work was supported by Glaxo Group Research Ltd., Greenford, UK     

A clinical and pharamcological study of high-dose mitozolomide given in conjunction with autologous bone marrow rescue

Summary In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i. v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m² over 1 h. Neutropaenia occurred consistently at 300 mg/m², and three trivial infective episodes were recorded. Thrombocytopaenia occurred consistently at 150 mg/m², and three patients experienced episodes of minor bleeding. The death of one subject was attributable to pulmonary thromboembolism during the bone marrow reinfusion. Transient emesis and mild alopecia were the only other toxicities. Three of six evaluable patients receiving 300 mg/m² exhibited measurable reductions in tumour dimensions, although these failed to fulfil the criteria for a partial response. Mitozolomide was undetectable in plasma at 12 h after drug administration. The plasma pharmacokinetic data fitted mono- or biexponential models in all patients. Model-independent pharmacokinetic parameters were: peak plasma drug concentration, 3.4–46 mg/l; AUC, 8–82 mg h l^–1; clearance, 7.6–45 l/h; steady-state volume of distribution, 11–85 l; and plasma elimination half-life, 1.4–2.8 h. Dose-dependent pharmacokinetics were not observed, and only a small percentage of the delivered dose was eliminated unchanged in the urine. The maximally tolerated dose of mitozolomide given with autologous bone marrow rescue was >400 mg/m². At this dose myelosuppression was the only major toxicity, and the plasma drug levels and AUC values were comparable to those obtained after therapeutic doses in experimental models.     

Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20–25–30 mg/m²; or 25–30–35 mg/m²; or 30–35–40 mg/m². The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25–75 years, WHO PS 2, normal haematology and biochemistry, life expectancy 3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade 3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m², and even up to 45 mg/m² when pooling data from another study. A pharmacokinetic–pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.     

A pharmacokinetic and pharmacodynamic study of the new anthracycline pirarubicin in breast cancer patients

Summary We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30–60 mg/m² according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m²) and continuous infusions of 5-fluorouracil (750 mg/m² daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a twocompartmental pattern, showing half-lives of 15.6 min and 16.6 h: the total plasma clearance of the drug was 140 l/h^–1/m^–2, and the total volume of distribution was 2,830 l/m². A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.     

Human pharmacokinetics of marcellomycin

Summary In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m². Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40–50 mg/m², the peak MCM concentration in plasma was 1.67±0.61 M; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 Mxh; plasma clearance of MCM was 1.50±0.88 l/min/m². Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m², fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40–50 mg/m², and to 7.0%±2.3% at 27.5 mg/m². No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.This work was presented in part at the Annual Meeting of the American Society of Clinical Oncology, San Diego, CA, May 1983     

Bleomycin clinical pharmacology by radioimmunoassay

Summary Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7–30 U intravenously (IV) and eight patients who received 4–30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m² and the volume of distribution was 13.2 l/m². Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m² and the volume of distribution was 19.2 l/m². Bleomycin plasma clearance correlated well with serum creatinine (r²=0.72).Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.     

Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1–17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min^–1 m^–2; range, 71–151 ml min^–1 m^–2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m² given as a 1-h infusion; 1,200 mg/m² divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m² given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both C_max (r=0.95) and AUC (r=0.97). The mean value ± SD for the dose-normalized AUC was 13±2 min m² l^–1 (n=57). The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m² achieved a similar AUC (13.78±2.90 and 15.05±1.44 mg ml^–1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r=0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r=0.52,P=0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed. A dosing formula appears unnecessary in children with normal renal function since a generally well-predictable free carboplatin AUC is achieved following a given dose.Supported by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)     

Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors

Summary The pharmacokinetics of carboplatin in cerebrospinal fluid (CSF) and plasma was studied in five children with brain tumors (four medulloblastomas and one ependimoblastoma) who underwent preirradiation treatment with carboplatin. Carboplatin pharmacokinetics was studied following the administration of 600 mg/m² as a 1-h infusion. Four children were treated a few weeks after surgery, whereas one child with an unresectable tumor was treated prior to surgery. All patients had a ventricular-peritoneal CSF shunt connected to a subcutaneous reservoir. Total platinum and free carboplatin were measured. The mean AUC values for free carboplatin in CSF and plasma were 2.29±1.20 and 8.18±1.27 mg ml^–1 min, respectively. The mean ratio of CSF AUC to plasma AUC was 0.28 (range, 0.17–0.46). Both plasma peak levels and AUC values showed limited interpatient variability. On the other hand, carboplatin levels in CSF showed substantial interpatient variability, with a>5-fold difference in peak levels and a 3-fold difference in AUC values being recorded. The interpatient difference in CSF pharmacokinetics may have been related at least in part to the different anatomical alterations induced by the surgical procedures or by the presence of a large tumor mass. In the four evaluable patients exhibiting macroscopic residual tumor, we observed one complete remission (CR) and two partial remissions (PR) following two cycles that consisted of two doses of 600 mg/m² carboplatin given on 2 consecutive days (total dose, 1200 mg/m²) and were separated by a l-month interval. These results may give some indication as to the optimal dose and schedule for carboplatin administration in the treatment of primitive neuroectodermic tumors (PNET).This work was partially supported by the AIRC     

Pharmacokinetics of high-dose busulfan in children

Summary The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4–14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803±228 ng/ml was achieved at 92–255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119±54 ml/min per m², with an apparent distribution volume of 27.10±11.50 l/m². A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25–7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5–1.4).     

Pharmacokinetics and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9–121 mol/kg (3–40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0±1.9 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 11.8±1.4 l/kg; and mean residence time (MRT), 0.56±0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters:C _c, 19.4±2.3 l h^–1 kg^–1; V_c, 7.08±1.06 l/kg;t _1/2 13.1±3.5 min; andt _1/2Z, 1.60±0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%–25.3% over the drug concentration range of 1–561 M. After the i.v. administration of 30 mol/kg [³H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a hight _1/2c value (37–59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; <1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mol/kg, all mice experienced clonic seizures for 2 min (with one death occuring) followed by a period of sedation that lasted for up to 2h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mol/kg) resulted in mortality, with death occurring within 2 min of AC administration.Supported by the Auckland Medical Research Foundation and the Cancer Society of New Zealand     

Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I–II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III–IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2×300 to 2×500 mg/m². Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination halflives of 4.15±2.57 and 28.8±12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96±2.89 to 12.22±3.95 mg l^–1h. Drug clearance was independent of the dose given and equal to 109±65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r=0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.     

The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion

It has often been reported that the oxazaphosphorines ifosfamide and cyclophosphamide induce their own metabolism. This phenomenon was studied in 21 paediatric patients over 35 courses of therapy. All patients received 9 g m^–2 of ifosfamide as a continuous infusion over 72 h. Plasma concentrations of parent drug and of the major metabolite in plasma, 3-dechloroethylifosfamide (3DC) were determined using a quantitative thin-layer chromatography (TLC) technique: A one-compartment model was fitted simultaneously to both ifosfamide and 3DC data. The model included a time-dependent clearance term, increasing asymptotically from an initial value to a final induced clearance and characterised by a first-order rate constant. A time lag, before induction of clearance began, was determined empirically. Metabolite kinetics were characterised by an elimination rate constant for the metabolite and a composite parameter comprising a formation clearance, proportional to the time-dependent clearance of parent drug, divided by the volume of distribution of the metabolite. Thus, the parameters to estimate were the volume of distribution of parent drug (V), initial clearance (Cli), final clearance (Cls), the rate constant for changing clearance (Kc), the elimination rate constant for the metabolite (Km) and Vm/fm, the metabolite volume of distribution divided by the fractional clearance to 3DC. The model of drug and metabolite kinetics produced a good fit to the data in 22 of 31 courses. In a further 4 courses an auto-inductive model for parent drug alone could be used. In the remaining courses, auto-induction could be demonstrated, but there were insufficient data to fit the model. For some patients this was due to a long time lag (up to 54 h) relative to the infusion time. The time lag varied from 6 to 54 (median, 12) h and values for the other parameters were Cli, 3.27±2.52 l h^–1m^–2, Cls, 7.50±3.03 l h^–1m^–2, V, 22.0±11.0 l m^–2,Kc, 0.086±0.074 h^–1;Km, 0.159±0.077 h^–1 and Vm/fm, 104±82 l m^–2. The values ofKc correspond to a halflife of change in clearance ranging from 2 to 157 h, although for the majority of the patients the half-life was less than 7 h and a new steady-state level was achieved during the 72 h infusion period. This model provides insight into the time course of enzyme induction during ifosfamide administration, which may continue for up to 10 days in some protocols. Since other drugs, including common anti-neoplastic agents, are metabolised by the same P450 enzyme as is ifosfamide, auto-induction may have implications for the scheduling of combined chemotherapy.     

Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients

Summary The pharmacokinetics and metabolism of cyclophosphamide were studied in nine paediatric patients. Plasma samples were obtained from eight subjects and urine was collected from six children during a 24-h period after drug administration. Cyclophosphamide and its major metabolites phosphoramide mustard (PM), carboxyphosphamide (CX), dechloroethylcyclophosphamide (DCCP) and 4-ketocyclophosphamide (KETO) were determined in plasma and urine using high-performance thin-layer chromatography-photographic densitometry (HPTLC-PD). Cyclophosphamide (CP) was nearly, if not completely, cleared from plasma by 24 h after its administration. The plasma half-life of CP ranged from 2.15 to 8.15 h; it decreased following higher doses and was shorter than that previously reported for adult patients. Both the apparent volume of distribution (0.49±1.4 l/kg) and the total body clearance (2.14±1.4 l m^–2 h^–1) increased with increasing dose. Renal clearance ranged between 0.12 and 0.58 l/h (mean, 0.43±0.19l/h). Between 5.4% and 86.1% of the total delivered dose was recovered as unchanged drug in the urine. The major metabolites identified in plasma and urine were PM and CX. One patient appeared to be deficient in CX formation. This study suggests that there is interpatient variability in the pharmacokinetics and metabolism of CP in paediatric patients. The shorter half-life and higher clearance as compared with adult values indicate faster CP metabolism in children.M.J.T. was supported by a grant from the Fondo de Investigacion Sanitaria, Ministerio de Sanidad y Consumo, Spain. This work was also supported in part by grants from the North of England Cancer Research Campaign, North of England Children's Cancer Research Fund, ASTA Werke Germany, and the Wellcome Trust.     

Pharmacokinetics of acridine-4-carboxamide in the rat,with extrapolation to humans

Summary The pharmacokinetics ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) were investigated in rats after i. v. administration of 18, 55 and 81 mol/kg [³H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (±SD) model-independent pharmacokinetic parameters were; clearance (Cl), 5.3±1.1 1 h^–1 kg^–1; steady-state volume of distribution (Vss), 7.8±3.0 l/kg; mean residence time (MRT), 1.5±0.4 h; and terminal elimination half-life (t _1/2Z), 2.1±0.7 h (n=10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1–8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05–0.10; 95% confidence limits) 1 h^–1 kg^–1 and a V_ss value of 0.63 (range, 0.2–1.1) l/kg for total drug concentrations in humans.